Patent EA-003397-B1 (EA)
Title: New derivatives of 6-(4-phenylbutoxy)hexylamine and process for producing salmeterol
Inventor: BESSA BELLMUNT JORDI
IPC: C07C223/02
Filed: 1999-09-20
Abstract: 1. A 6-(4-phenylbutoxy)hexylamine derivative compound of the general formula (I): wherein: R1 is CHO or CHOR3OR4, where R3 and R4 independently are C1-C6 alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals; and R2 is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group. 2. A compound as claimed in Claim 1 characterized in that R1 being equal to CHO, R2 is an alkyloxycarbonyl-, aryloxycarbonyl-, aralkyloxycarbonyl- or acyl group. 3. A compound as claimed in Claim 1, characterized in that R3 and R4 independently are methyl, ethyl, benzyl, or they form either 1,3-dioxolanes or 1,3-dioxanes. 4. A compound as claimed in any one of Claims 1 or 2, characterized in that R2 is tert-butoxycarbonyl-, benzyloxycarbonyl-, ethoxycarbonyl-, acetyl-, benzoyl- or trifluoroacetyl. 5. A process for the obtention of salmeterol or its pharmaceutically acceptable salts, characterized in that reaction of an organometallic compound of the general formula (13) is carried out with a synthetic intermediate groups of the general formula (I) as claimed in claim 1 in an inert solvent at low temperature between -40 to 40 degree C followed by hydrolysis and removal of the protecting wherein M is a group containing a metal selected from lithium, magnesium or copper. 6. A process as claimed in Claim 5, characterized in that said inert solvent is an ether such as ethyl ether or tetrahydrofuran. 7. A process as claimed in Claim 5, characterized in that said reaction is carried out at a temperature ranging from -40 DEG C to 40 DEG C, preferably from -40 degree C to 10 degree C. 8. A process as claimed in Claim 5, characterized in that R3 and R4 independently are methyl, ethyl, benzyl, 2,2-dimethyl-1,3-dioxane or 2-methyl-1,3-dioxane. 9. A process as claimed in Claim 5, characterized in that M is Li, MgBr or MgCl. 10. A process for the obtention of a 6-(4-phenylbutoxy)hexylamine derivative compound of the general formula (I) as claimed in anyone of Claims 1 to 4, characterized in that the following steps are performed: (i) alkylation of an amine by reaction of a compound of the formula (11) with a compound of the formula (12) wherein: R3 and R4 independently are C1-C6 alkyl-, aralkyl, or they form 5 or 6 membered cyclic acetals; and Z1 and Z2 are each different and the same as L or NHR2, L being a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy- or p-toluenesulfonyloxy; and R2 is H or benzyl; in an inert solvent in the presence of an organic or inorganic base at a temperature ranging from 25 to 110 degree C, to yield the compound of the general formula (I) wherein R1 is CHOR3OR4, and R3 is H or benzyl; (ii) protection of the amino group of the compound obtained in step (i) with a suitable reagent, with previous hydrogenation when R is benzyl, in an inert solvent, optionally in the presence of an organic or inorganic base, at a temperature ranging from 0 degree C to 50 degree C, for the obtention of the compound of the formula (I) where R1 = CHOR3OR4- group and R2 = alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group; (iii) conversion of the compound obtained in step (ii) into the corresponding aldehyde by hydrolysis, transacetalization or hydrogenolysis of the acetal group, for the obtention of the compound of the general formula (I) wherein R1 = CHO-group and R2 = alkyloxycarbonyl-, aryloxycarbonyl-, aralkyloxycarbonyl-, or an acyl group. 11. A process as claimed in Claim 10, characterized in that in step (i) the inert solvent is selected from a high boiling-point aprotic solvent such as N,N-dimethylformamide, N-methylpirrolidone or dimethylsulfoxide, or a halogenated solvent such as methylene chloride or chloroform, or an ether such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene, toluene or xylene. 12. A process as claimed in Claim 10, characterized in that in step (i) and (ii) the organic base is selected from a tertiary amine such as triethylamine or diisopropylamine, an aromatic amine such as N,N-dimethylaniline, or a heterocyclic amine such as pyridine, or a carbonate or bicarbonate. 13. A process as claimed in Claim 10, characterized in that in step (ii) said reagent is selected from a chloroformate such as ethyl chloroformate, tert-butyl chloroformate or benzyl chloroformate; a dicarbonate such as di-tert-butyl dicarbonate or dibenzyl dicarbonate; or specific reagents such as N-(benzyloxycarbonyloxy)succinimide; or an acid chloride or an anhydride. 14. A process as claimed in claim 10, characterized in that in step (ii) the inert solvent is selected from a ketone such as acetone, a halogenated derivative such as methylene chloride or chloroform, an ester such as ethyl acetate, an ether such as tetrahydrofuran or dioxane, or a high boiling-point solvent such as N,N-dimethylacetamide or N,N-dimethylformamide. 15. A process as claimed in Claim 10, characterized in that in step (iii) the hydrolysis reaction is carried out in an organic solvent in the presence of an at least stoichiometric amount of water, and an organic or inorganic acid. 16. A process as claimed in Claim 10, characterized in that in step (iii) the transacetalization reaction is carried out in the presence of a ketone and an organic or inorganic acid. 17. A process as claimed in anyone of Claims 15 or 16, wherein the reaction is performed in the presence of hydrochloric, sulfuric, methanesulfonic, p-toluenesulfonic or trifluoroacetic acid, at a temperature ranging from 15 degree C to 50 degree C. 18. A process as claimed in Claim 10, characterized in that in step (iii) the hydrogenolysis reaction is carried out in the presence of a catalyst in an inert solvent, at a temperature ranging from 10 degree C to 50 degree C. 19. A process as claimed in Claim 18, wherein the catalyst is palladium. 20. A process as claimed in Claim 18, wherein the solvent is selected from a C1 to C4 aliphatic alcohol such as methanol, ethanol, isopropanol or butanol, an ester such as ethyl acetate, or an ether such as tetrahydrofuran.